The present invention relates to fused thiophene derivatives and inhibitors of producing Interleukin-6 (abbreviated as IL-6 hereafter) and/or Interleukin-12 (abbreviated as IL-12 hereafter) containing fused thiophene derivatives as an active ingredient.
More particularly, the present invention relates to inhibitors of producing IL-6 and/or IL-12 comprising, as an active ingredient, fused thiophene derivatives of the formula (I) 
(wherein all the symbols are as defined hereafter.)
and non-toxic salts thereof, novel fused thiophene derivatives of the said formula (IA) or non-toxic salts thereof and methods for preparation thereof.
Moreover, the present invention relates to a method for preparation of a compound of the formula (XI) which is an intermediate for the compounds of the formula (I).
Cytokine is a multifunctional factor which plays an important role in the host defence system of living body and it relates to various life phenomena. However, there are many diseases which may be caused by overproduction thereof or by overresponse thereto.
IL-6 is a cytokine produced from various cells, e.g. T cells, B cells, macrophages, kidney mesangial cells, fibroblasts etc., and its various physiological effects are known e.g. induction of B cell differentiation to antibody-producing cells, activation of T cells, increase of platelets, and production of acute phase protein from liver cells etc. But, an abnormal production of IL-6 has been observed in various inflammations, autoimmune diseases and neoplastic diseases and it is suggested that IL-6 plays a certain role in the causes of such pathophysiological situations. In the experiment using an animal model in which IL-6 was forcibly expressed, various types of diseases could be observed and such results strongly suggest the existence of relationship between the abnormal production of IL-6 and the cause of certain diseases (Biochem. J., 265, 621 (1990), Immunol. Today, 11, 443 (1990), J. Autoimmun., 5 Suppl A, 123 (1992), Clin. Immunol. Immunopathol., 62, S60 (1992)).
IL-12 is a cytokine produced from macrophages and dendritic cells etc. and its effects are known; e.g. activation of natural killer (abbreviated as NK hereafter) cells, induction of Interferon-xcex3 (abbreviated as IFN-xcex3 hereafter) production from NK cells and T cells, and regulation of Th1 and Th2 balance etc. Helper T cells are classified into Th1 which stimulates cellular-mediated immunity and Th2 which assists humoral immunity. IL-12 functions to induce Th1 from helper T cell precursors. It is thought that succeedingly, IL-12 induces production of IFN-xcex3 from Th1 cells (which are further differentiated) and accelerates killer activity, so that IL-12 plays a role as a main cytokine causing inflammatory immune reaction which leads to organ disorders (Blood, 84, 4008 (1994)).
Therefore, inhibition of IL-6 and/or IL-12 production(s) is expected to improve various kinds of diseases such as inflammatory diseases as a representative. The present invention is targeted for these cytokines and provides novel medicines through inhibiting the production thereof.
Clinical application of the compounds of the present invention involves those diseases which may be. caused and be changed to worse by abnormal production of IL-6 and/or IL-12 or by overresponse to them. Inhibitors of producing IL-6 may be used for the prevention and/or treatment of various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi""s sarcoma, rheumatoid arthritis, gammopathy, Castleman""s disease, atrial myxoma, diabetes mellitus, autoimmune diseases (J. Immunol., 145, 4185 (1990), J. Exp. Med, 172 1505 (1990), J. Clin. Invest., 87, 739 (1991), J. Clin. Invest., 8.9 1681 (1992), EMBO J., 1, 1189 (1994), Hematol. Oncol. Clin. North Am., 11, 159 (1997)). Inhibitors of producing IL-12 may be used for the prevention and/or treatment of various inflammatory diseases, diabetes mellitus, hepatitis, multiple sclerosis, colitis, graft versus host immune diseases, rheumatoid arthritis, infectious diseases, autoimmune diseases (J. Exp. Med., 181, 817 (1995), J. Exp. Med., 181, 381 (1995), J. Exp. Med., 182, 1281 (1995), Ann, NY Acad. Sci., 795, 371 (1996), Int. Immunol., 8, 569 (1996), Proc. Natl. Acad. Sci. USA, 92, 4823 (1996)).
Further, a compound of the formula (XI) is an important intermediate of pharmaceutical agents and an efficient method for preparation thereof has been desired.
For example,
(1) In the specifications of U.S. Pat. Nos. 3,629,438 and U.S. Pat. No. 3,686,216, it is disclosed that a benzothiophene-1,1-dioxide derivative of the formula (X) 
(wherein Xx is halogen, nitro, alkyl, alkoxy, haloalkyl, carboxy or sulfonylhalide,
Yx is hydrogen, lower alkyl, lower alkoxy, halogen or hydroxy,
Zx is alkyl, alkoxy, halogen, carboxy, haloalkyl or nitro,
aX is 0 or an integer of 2,
bX is an integer of 2,
cX is 0 or an integer of 1xcx9c5 or
dX is 0 or an integer of 1xcx9c4.)
has an anti-fungal and anti-vital activities.
(2) In the specification of FR1585930, a compound of the formula (Y) 
(wherein R1Y is hydrogen, halogen or C1xcx9c3 alkyl; R2Y and R3Y are hydrogen or C1xcx9c3 alkyl) is described as an intermediate of diuretic agent, but there is no description about its biological activity.
(3) In the specification of SU591474, it is described that a compound of the formula (Z) 
(wherein RZ, R1Z, R2Z and R3Z are hydrogen or methyl.) has an anti-spasm activity.
(4) In the specification of EP50326, it is described that a compound of the formula U 
(wherein R1U and R2U are each hydrogen or C1xcx9c6 alkyl, C3xcx9c6 cycloalkyl or phenyl which may be substituted with 1xcx9c2 of halogen, hydroxy, C1xcx9c6 alkyl or alkoxy, R3U is hydrogen or ZU, ZU is C1xcx9c6 alkyl or CR4UR5UR6U, R4U and R5U are hydrogen or C1xcx9c6 alkyl, R6U is COOH, CH2xe2x80x94OH, C1xcx9c6 alkoxycarbonyl or hydroxyaminocarbonyl, XU is hydrogen, halogen or C1xcx9c6 alkyl, nU is 1 or 2, mU is 0xcx9c2) has a diuretic activity (In the explanation of groups, essential parts are extracted).
(5) In the specification of WO9527710, it is described that a compound of the formula (V) 
(wherein R1V is t-butyl, R1V is hydrogen, lower alkyl or acyl, a broken line is arbitrary bond, R2V and R3V are hydrogen, alkyl which may be substituted or alkenyl which may be substituted, R4V does not represent anything when arbitrary bond exists and represents the same meaning as R3V when arbitrary bond does not exist and nV is 0xcx9c2.) has an activity as antioxidant of low-density lipoprotein (LDL) (In the explanation of groups, essential parts are extracted).
(6) In the specification of Japanese Patent Application Kokai Hei 10-298180, it is described that a compound of the formula (W) 
(wherein AZ is 
(wherein ZW is oxygen atom or sulfur atom; R1W, R2W, R3W and R4W are the same or different, are hydrogen etc.); EW and FW are the same or different, are nitrogen atom or CH which may be substituted with XW or YW; XW is straight or branched C1-6 alkyloxy, C3-8 cycloalkyloxy or straight or branched C1-3 alkyloxy substituted with C3-8 cycloalkyl; Y is 
(wherein GW is xe2x80x94CONHxe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94NHCOxe2x80x94 or xe2x80x94OC(O)xe2x80x94; R5W is (a) straight or branched C1-6 alkyl, (b) C3-8 cycloalkyl, (c) C7-12 spiroalkyl, (d) C7-12 bicycloalkyl, (e) aryl, (f aralkyl, (g) heteroarylalkyl, (h) non-aromatic heterocyclic ring which may be substituted with phenyl or (i) C3-8 cycloalkyl-C1-3 alkyl. Each of them may be substituted with one or more of substituent selected from a group consisting of i) straight or branched C1-6 alkyl, ii) straight or branched C1-8 alkyloxy, iii) C1-3 haloalkyl, iv) halogen, v) C3-8 cycloalkyl, vi) carboxy, vii) alkyloxycarbonyl, viii) acyl, ix) formyl and x) nitro; nW is an integer of 1-3, pW is an integer of 1-3, (CH2)nW and (CH2)pW may be substituted with a straight or branched C1-6 alkyl or C1-3 haloalkyl) has an antagonistic activity against dopamine receptor.
(7) In the specification of Japanese Patent Application Kokai Hei 10-513470, it is described that a compound of the formula (T) 
[wherein R1T and R3T are independently hydrogen, xe2x80x94CH3, xe2x80x94C(O)xe2x80x94(C1xcx9c6 alkyl), or xe2x80x94C(O)xe2x80x94ArT (ArT is phenyl which may optionally be substituted); R2T is selected from a group consisting of pyrrolidino, hexamethyleneimino and piperidino], a pharmaceutically acceptable salt thereof or a solvent additive has an activity of inhibiting the effect of IL-6.
(8) In the specification of Japanese Patent Application Kokai Hei 11-49765, it is described that a compound of the formula (S) 
(wherein each R1S and R2S is hydrogen or hydrocarbon group which may contain substituent(s) or R1S and R2S taken together with the neighboring carbon atom represents 3- to 8-membered homo or heterocyclic ring which may contain substituent(s), R3S is hydrogen or lower alkyl which may contain subtstituent(s) or aromatic group which may contain substituent(s), R4S is (1) aromatic group which may contain substituent(s), (2) aliphatic hydrocarbon which contains aromatic group (this group is unsubstituted or substituted.) and which may contain additional substituent(s) or (3) acyl, XS and YS are each oxygen atom or sulfur atom which may be oxidized, 
is single bond or double bond, ring AS is benzene ring which contains a group of the formula xe2x80x94XSxe2x80x94R4S (wherein each symbols represent the same meaning as defined hereinbefore) and which may contain additional substituent(s), with the proviso that when  is single bond and both XS and YS are oxygen atom, then R4S is not acyl.] or a salt thereof have an excellent inhibitory effect of neurodegeneration.
(9) Further, the following compounds are known.
Compound (1): 3-(Thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08156),
Compound (2): 6-Nitro-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, catalog No. KM 08165),
Compound (3): 3-(Thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08138),
Compound (4): 3-Phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08140),
Compound (5): 4,5-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-04-4),
Compound (6): 4,6-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-05-5),
Compound (7): 4,7-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-06-6),
Compound (8): 5,6-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-07-7),
Compound (9): 5,7-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-08-8),
Compound (10): 6,7-Dimethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102036-09-9),
Compound (11): 4-Carboxymethyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 102539-83-3),
Compound (12): 6-(2,2-Bis(ethoxycarbonyl)ethenyl)amino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 118675-43-7),
Compound (13): 4-Methylaminocarbonyloxy-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 13687-26-8),
Compound (14): 5-(2-(N-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamino)ethyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 188110-86-3),
Compound (15): 5-(2-Hydroxyethyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 188111-49-1),
Compound (16): 5-Bromo-7-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-24-5),
Compound (17): 7-Bromo-5-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-25-6),
Compound (18): 5-Bromo-6-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-26-7),
Compound (19): 5-Bromo-4-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-27-8),
Compound (20): 6-Bromo-5-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-28-9),
Compound (21): 4-Bromo-5-methyl-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 19076-29-0),
Compound (22): 6-Amino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 20503-40-6),
Compound (23): 6-Acetyamino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 20503-41-7),
Compound (24): 6-(4-Diethylaminophenyl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 33431-95-7),
Compound (25): 1,1-Dioxidethieno[2,3-b]pyridine (CAS Registry No. 37049-39-1),
Compound (26): 1,1-Dioxidethieno[3,2-b]pyridine (CAS Registry No. 37049-40-4),
Compound (27): 1,1-Dioxidethieno[2,3-c]pyridine (CAS Registry No. 37049-41-5),
Compound (28): 5-Amino-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 51956-01-5),
Compound (29): 5-(3-Methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1,1-dioxidebenzo[b]thiophene (CAS Registry No. 51956-06-0),
Compound (30): 4-(2-(1,1-Dioxidebenzo[b]thiophen-3-yl)ethyl)-1,1dioxidebenzo[b]thiophene (CAS Registry No. 57011-92-4),
Compound (31) 7-Methyl-1,1-dioxidethieno[2,3-c]pyridine (CAS Registry No. 76905-90-3),
Compound (32): 1,1-Dioxidebenzo[b]thiophene (CAS Registry No. 825-44-5),
Compound (33): 4-(4-Methoxyphenyl)-1,1-dioxidethieno[3,2-c]pyridine (CAS Registry No. 97104-25-1).
(10) In addition, as to a method for preparation of a compound of the formula (XI), for example, the method of the following Reaction Scheme 2 is known.
These are described in detail in Nihonkagakuzasshi 1966, 87(2),186-1 89, J. Org. Chem., 1953, Vol.18, 1511 and J. Org. Chem. 1973, Vol.38,146. 
In Reaction Scheme 2, Me is methyl, Ac is acetyl and NBS is N-bromosuccinimide.
The above method of Reaction Scheme 2 requires 5 or 6 steps in total and Ag2O, which is an expensive reagent, in oxidation reaction from the compound of the formula (XI-A-6) to the compound of the formula (XI).
Further, in the specification of Japanese Patent Application Kokai Hei 6-49058, the following Reaction Scheme 3 is disclosed as a method for preparation of the compound of the formula (XI). 
In Reaction Scheme 3, Et is ethyl.
The above method of Reaction Scheme 3 requires 5 steps in total and the total yield is around 2xcx9c3%.
In Tetrahedron Letters, 1996, Vol.37, No.19, 3243 and Tetrahedron Letters 1990, Vol.31, No.28, 401 1, a reaction wherein ketone is converted into nitrile, followed by dehydrogenation to give aromatic ring is disclosed (Reaction Scheme 4). 
In Reaction Scheme 4, TMS is trimethylsilyl, DDQ is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
This reaction is a method for preparation of aromatic nitrile of the formula (XI-C-2) which comprises that cyclic ketone of the formula (XI-C-1) is converted into cyanohydrin, followed by dehydration to give nitrile of the formula (XI-C-2), and then followed by dehydrogenation by an oxidizer.
The present inventors have investigated to find new compounds possessing an inhibitory activity of producing IL-6 and/or IL-12, so that the present inventors have found that the purpose has been achieved by fused thiophene derivatives of the formula (I).
Fused heterocyclic compounds of the formula (I) of the present invention has not been known as inhibitors of producing IL-6 and/or IL-12 at all. Further, a fused thiophene derivative of the formula (IA) is a novel compound which is not known at all.
In addition, the present inventors have investigated to find an efficient method for preparation at a low cost, so that the present inventor have found a method of the following Reaction Scheme 5. 
The old methods require 5-6 steps, whereas the method of the present invention diminishes to 3 steps in total, so it become possible to produce efficiently. In addition, it is also confirmed that in mass-production of it, the cost for the production is reduced, so that the present inventors have completed the present invention.
The present invention relates to
(1) an inhibitor of producing Interleukin-6 and/or Interleukin-12 comprising, as an active ingredient, a fused thiophene derivative of the formula (I) 
[wherein  is a single or double bond,
Y is (i) 
or
(ii) hydrogen
(with a proviso that when  is a double bond, Y is hydrogen, and when  is a single bond, Y is 
m and n are each independently 0 or an integer of 1-2,
p is 0 or an integer of 1-4,
q is 0 or an integer of 1-5,
Z is single bond, C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene, 
xe2x80x83is
(i) benzene ring or
(ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s), 
xe2x80x83is
(i) C3-15 mono-, bi- or tricyclic carbo ring or
(ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, each R1 of (R1)p is independently,
(i) C1-8 alkyl,
(ii) C2-8 alkenyl,
(iii) C2-8 alkynyl,
(iv) nitro,
(v) cyano,
(vi) halogen,
(vii) Cyc1,
(viii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen or Cyc1 or
(ix) xe2x80x94A1xe2x80x94A2xe2x80x94A3,
A1 is
(i) single bond,
(ii) C1-8 alkylene,
(iii) C2-8 alkenylene or
(iv) C2-8 alkynylene,
A2 is
xe2x80x94Oxe2x80x94,
(ii) xe2x80x94NR3xe2x80x94,
(iii) xe2x80x94C(O)xe2x80x94,
(iv) xe2x80x94CH(OH)xe2x80x94,
(v) xe2x80x94C(O)NR4xe2x80x94,
(vi) xe2x80x94NR5C(O)xe2x80x94,
(vii) xe2x80x94C(O)Oxe2x80x94,
(viii) xe2x80x94OC(O)xe2x80x94,
(ix) xe2x80x94SO2NR6xe2x80x94,
(x) xe2x80x94NR7SO2xe2x80x94,
(xi) xe2x80x94C(O)NR9Oxe2x80x94,
(xii) xe2x80x94OC(O)NR10xe2x80x94,
(xiii) xe2x80x94NR11C(O)NR12xe2x80x94,
(xiv) xe2x80x94NR13C(O)Oxe2x80x94 or
(xv) xe2x80x94OC(O)Oxe2x80x94
(wherein R3, R4, R5, R6, R7, R9, R10, R11, R12 and R13 are each independently, hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with Cyc1, xe2x80x94OR14 (wherein R14 is hydrogen or C1-8 alkyl.) or cyano, with the proviso that the linkage of the right side of each group represented by A2 binds to A3.
A3 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) Cyc1 or
(vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1-3 groups selected from the following (a)-(i):
(a) halogen,
(b) cyano,
(c) xe2x80x94P(O)(R15)2,
(d) xe2x80x94Si(R16)3,
(e) Cyc1,
(f) xe2x80x94C(O)R17,
(g) xe2x80x94OR18,
(h) xe2x80x94NR19R20,
(i) xe2x80x94SR21;
plural R15s are each independently, hydroxy or C1-8 alkoxy,
plural R16s are each independently C1-8 alkyl,
R17 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) hydroxy,
(iv) C1-8 alkoxy,
(v) Cyc1 or
(vi) xe2x80x94NR22R23 (wherein R22 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl, R23 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25(R24 and R25 are each independently hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted with phenyl.).),
R18 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) Cyc1 or
(v) C1-8 alkyl substituted with Cyc1, Si(R26)3 (wherein plural R26s are each independently C1-8 alkyl.) or xe2x80x94OR27 (wherein R27 is hydrogen, C1-8 alkyl or C2-5 acyl.),
R19 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) phenyl or
(iv) C1-8 alkyl substituted with phenyl,
R20 is
(i) hydrogen,
(ii) C1-8 alkyl or
(iii) xe2x80x94C(O)R28 (wherein R28 is C1-8 alkyl, C1-8 alkoxy, Cyc1 or NR29R30 (wherein R29 and R30 are each independently, hydrogen or C1-8 alkyl.).),
(iv) Cyc1 or
(v) C1-8 alkyl substituted with Cyc1 or cyano,
R21 is
(i) hydrogen,
(ii) C1-8 alkyl or
(iii) Cyc1,
Cyc1 is
(i) C3-15 mono-, bi- or tricyclic carbo ring or
(ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) diphenylmethyl, (xi) triphenylmethyl, (xii) Cyc2, (xiii) xe2x80x94OR31, (xiv) xe2x80x94SR32, (xv) xe2x80x94NR33R34, (xvi)xe2x80x94SO2NR35R36, (xvii) xe2x80x94C(O)R37 or (xviii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc2, hydroxy, halogen or xe2x80x94C(O)xe2x80x94Cyc2,
R31 and R32 are each independently, hydrogen, C1-8 alkyl or Cyc2,
R33 is hydrogen or C1-8 alkyl,
R34 is hydrogen, C1-8 alkyl or xe2x80x94C(O)xe2x80x94Cyc2,
R35 is hydrogen or C1-8 alkyl,
R36 is hydrogen, C1-8 alkyl or Cyc2,
R37 is hydrogen, C1-8 alkyl, xe2x80x94OR38, xe2x80x94NR39R40, Cyc2, or C1-8 alkyl substituted with Cyc2 or xe2x80x94C(O)xe2x80x94Cyc2,
R38, R39 and R40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc2,
Cyc2 is
(i) C3-15 mono-, bi- or tricyclic carbo ring or
(ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) xe2x80x94OR41, (xi) xe2x80x94SR42, (xii) xe2x80x94NR43R44, (xiii) xe2x80x94SO2NR45R46, (xiv) xe2x80x94C(O)R47, (xv) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with hydroxy or halogen or (xvi) phenyl,
R41, R42, R43, R44, R45 and R46 are each independently, hydrogen or C1-8 alkyl,
R47 is hydrogen, C1-8 alkyl or C1-8 alkoxy
each R2 of (R2)q is independently,
(i) C1-8 alkyl,
(ii) C2-8 alkenyl,
(iii) C2-8 alkynyl,
(iv) xe2x80x94OR48,
(v) xe2x80x94NR49R50,
(vi) xe2x80x94C(O)R51,
(vii) nitro,
(viii) cyano,
(ix) halogen or
(x) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with xe2x80x94OR48, xe2x80x94NR49R50, xe2x80x94C(O)R51, halogen or Cyc3,
R48 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) Cyc3 or
(vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen, xe2x80x94OR52, xe2x80x94NR53R54, xe2x80x94C(O)R55 or Cyc3,
R49 and R50 are each independently, hydrogen, C1-8 alkyl or xe2x80x94COR59,
R51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or xe2x80x94NR60R61,
R52 is hydrogen, C1-8 alkyl, Cyc3, or C1-8 alkyl substituted with Cyc3,
R53 and R54 are each independently, hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or xe2x80x94C(O)R56 (wherein R56 is C1-8 alkyl, C1-8 alkoxy, Cyc3, or C1-8 alkyl substituted with Cyc3),
R55 is hydroxy, C1-8 alkoxy, or xe2x80x94NR57R58 (wherein R57 and R58 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc3),
R59 is C1-8 alkyl or C1-8 alkoxy,
R60 and R61 are each independently, hydrogen or C1-8 alkyl,
Cyc3 is
(i) C3-15 mono-, bi- or tricyclic carbo ring or
(ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) halogen, (v) cyano, (vi) hydroxy, (vii) benzyloxy, (viii) xe2x80x94NR62R63, (ix) xe2x80x94COOR64, (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenoxy, (xiv) phenylthio, (xv) C1-8 alkyl or C1-8 alkoxy substituted with phenyl, phenoxy, phenylthio, hydroxy, xe2x80x94NR62R63 or xe2x80x94COOR64,
R62 and R63 are each independently, hydrogen or C1-8 alkyl,
R64 is hydrogen or C1-8 alkyl, with the proviso that when A2 is (vi) xe2x80x94NR5C(O)xe2x80x94, (x) xe2x80x94NR7SO2xe2x80x94, (xiv) xe2x80x94NR13C(O)Oxe2x80x94 or (xv) xe2x80x94OC(O)Oxe2x80x94, then A3 is not hydrogen.],
an N-oxide derivative thereof or a non-toxic salt thereof,
(2) a fused thiophene derivative of the formula (IA) 
[wherein  is a single or double bond,
Y is
(i) 
xe2x80x83or
(ii) hydrogen
(with a proviso that when  is a double bond, Y is hydrogen, and when  is a double bond, Y is hydrogen, and when  is a single bond, Y is 
m and n are each independently 0 or an integer of 1-2,
p is 0 or an integer of 1-4,
q is 0 or an integer of 1-5,
Z is single bond, C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene, 
xe2x80x83is
(i) benzene ring or
(ii) 6-membered monocyclic hetero aryl containing 1-2 nitrogen atom(s), 
xe2x80x83is
(i) C3-15 mono-, bi- or tricyclic carbo ring or
(ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom, each R1 of (R1)p is independently,
(i) C1-8 alkyl,
(ii) C2-8 alkenyl,
(iii) C2-8 alkynyl,
(iv) nitro,
(v) cyano,
(vi) halogen,
(vii) Cyc1,
(viii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen or Cyc1 or
(ix) xe2x80x94A1xe2x80x94A2xe2x80x94A3,
A1 is
(i) single bond,
(ii) C1-8 alkylene,
(iii) C2-8 alkenylene or
(iv) C2-8 alkynylene,
A2 is
(i) xe2x80x94Oxe2x80x94,
(ii) xe2x80x94NR3,
(iii) xe2x80x94C(O)xe2x80x94,
(iv) xe2x80x94CH(OH)xe2x80x94,
(v) xe2x80x94C(O)NR4xe2x80x94,
(vi) xe2x80x94NR5C(O)xe2x80x94,
(vii) xe2x80x94C(O)Oxe2x80x94,
(viii) xe2x80x94OC(O)xe2x80x94,
(ix) xe2x80x94SO2NR6xe2x80x94,
(x) xe2x80x94NR7SO2xe2x80x94,
(xi) xe2x80x94C(O)NR9Oxe2x80x94,
(xii) xe2x80x94OC(O)NR10xe2x80x94,
(xiii) xe2x80x94NR11C(O)NR12xe2x80x94,
(xiv) xe2x80x94NR13C(O)Oxe2x80x94 or
(xv) xe2x80x94OC(O)Oxe2x80x94
(wherein R3, R4, R5, R6, R7, R9, R10, R11, R12 and R13 are each independently hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with Cyc1, xe2x80x94OR14 (wherein R14 is hydrogen or C1-8 alkyl.) or cyano, with the proviso that the linkage of the right side of each group represented by A2 binds to A3.
A3 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) Cyc1 or
(vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1-3 groups selected from the following (a)-(i):
(a) halogen,
(b) cyano,
(c) xe2x80x94P(O) (R15)2,
(d) xe2x80x94Si(R16)3,
(e) Cyc1,
(f) xe2x80x94C(O)R17,
(g) xe2x80x94OR18,
(h) xe2x80x94NR19R20,
(i) xe2x80x94SR21;
plural R15s are each independently, hydroxy or C1-8 alkoxy,
plural R16s are each independently C1-8 alkyl,
R17 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) hydroxy,
(iv) C1-8 alkoxy,
(v) Cyc1 or
(vi) xe2x80x94NR22R23 (wherein R22 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl, R23 is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted with Cyc1 or NR24R25 (R24 and R25 are each independently hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted with phenyl.).),
R18 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) Cyc1 or
(v) C1-8 alkyl substituted with Cyc1, Si(R26)3 (wherein plural R26s are each independently C1-8 alkyl.) or xe2x80x94OR27 (wherein R27 is hydrogen, C1-8 alkyl or C2-5 acyl.),
R19 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) phenyl or
(iv) C1-8 alkyl substituted with phenyl,
R20 is
(i) hydrogen,
(ii) C1-8 alkyl or
(iii) xe2x80x94C(O)R28 (wherein R28 is C1-8 alkyl, C1-8 alkoxy, Cyc1 or NR29R30 (wherein R29 and R30 are each independently, hydrogen or C1-8 alkyl.).),
(iv) Cyc1 or
(v) C1-8 alkyl substituted with Cyc1 or cyano,
R21 is
(i) hydrogen,
(ii) C1-8 alkyl or
(iii) Cyc1,
Cyc1 is
(i) C3-15 mono-, bi- or tricyclic carbo ring or
(ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) diphenylmethyl, (xi) triphenylmethyl, (xii) Cyc2, (xiii) xe2x80x94OR31, (xiv) xe2x80x94SR32, (xv) xe2x80x94NR33R34, (xvi)xe2x80x94SO2NR35R36, (xvii) xe2x80x94C(O)R37 or (xviii) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with Cyc2, hydroxy, halogen or xe2x80x94C(O)xe2x80x94Cyc2,
R31 and R32 are each independently, hydrogen, C1-8 alkyl or Cyc2,
R33 is hydrogen or C1-8 alkyl,
R34 is hydrogen, C1-8 alkyl or xe2x80x94C(O)xe2x80x94Cyc2,
R35 is hydrogen or C1-8 alkyl,
R36 is hydrogen, C1-8 alkyl or Cyc2,
R37 is hydrogen, C1-8 alkyl, xe2x80x94OR38, xe2x80x94NR39R40, Cyc2, or C1-8 alkyl substituted with Cyc2, or xe2x80x94C(O)xe2x80x94Cyc2,
R38, R39 and R40 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc2,
Cyc2 is
(i) C3-15 mono-, bi- or tricyclic carbo ring or
(ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
the said carbocyclic ring or heterocyclic ring may be substituted with one or more of (i) C1-8 alkyl, (ii) C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) oxo, (v) cyano, (vi) nitro, (vii) trihalomethyl, (viii) trihalomethoxy, (ix) halogen, (x) xe2x80x94OR41, (xi) xe2x80x94SR42, (xii) xe2x80x94NR43R44, (xiii) xe2x80x94SO2NR45R46, (xiv) xe2x80x94C(O)R47, (xv) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with hydroxy or halogen or (xvi) phenyl,
R41, R42, R43, R44, R45 and R46 are each independently, hydrogen or C1-8 alkyl,
R47 is hydrogen, C1-8 alkyl or C1-8 alkoxy
each R2 of (R2)q is independently,
(i) C1-8 alkyl,
(ii) C2-8 alkenyl,
(iii) C2-8 alkynyl,
(iv) xe2x80x94OR48,
(v) xe2x80x94NR49R50,
(vi) xe2x80x94C(O)R51,
(vii) nitro,
(viii) cyano,
(ix) halogen or
(x) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with xe2x80x94OR48, xe2x80x94NR49R50, xe2x80x94C(O)R51, halogen or Cyc3,
R48 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) Cyc3 or
(vi) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with halogen, xe2x80x94OR52, xe2x80x94
NR53R54, xe2x80x94C(O)R; or Cyc3,
R49 and R50; are each independently, hydrogen. C1-8 alkyl or xe2x80x94COR59,
R51 is hydrogen, C1-8 alkyl, hydroxy, C1-8 alkoxy or xe2x80x94NR60R61,
R52 is hydrogen, C1-8 alkyl, Cyc3, or C1-8 alkyl substituted with Cyc3,
R53 and R54 are each independently, hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or xe2x80x94C(O)R56 (wherein R56 is C1-8 alkyl, C1-8 alkoxy, Cyc3, or C1-8 alkyl substituted with Cyc3),
R55 is hydroxy, C1-8 alkoxy, or xe2x80x94NR57R58 (wherein R57 and R58 are each independently, hydrogen, C1-8 alkyl, or C1-8 alkyl substituted with Cyc3),
R59 is C1-8 alkyl or C1-8 alkoxy,
R60 and R61 are each independently, hydrogen or C1-8 alkyl,
Cyc3 is
(i) C3-15 mono-, bi- or tricyclic carbo ring or
(ii) 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom,
the said carbocyclic ring or heterocyclic ring may be substituted with one or more of
(i) C1-8 alkyl, (ii) C1-8 alkoxy, (iii) nitro, (iv) halogen, (v) cyano, (vi) hydroxy, (vii) benzyloxy, (viii) xe2x80x94NR62R63, (ix) xe2x80x94COOR64, (x) trihalomethyl, (xi) trihalomethoxy, (xii) phenyl, (xiii) phenoxy, (xiv) phenylthio, (xv) C1-8 alkyl or C1-8 alkoxy substituted with phenyl, phenoxy, phenylthio, hydroxy, xe2x80x94NR62R63 or xe2x80x94COOR64,
R62 and R63 are each independently, hydrogen or C1-8 alkyl,
R64 is hydrogen or C1-8 alkyl,
with the proviso that when
(1) when A2 is (vi) xe2x80x94NR5C(O)xe2x80x94, (x) xe2x80x94NR7SO2xe2x80x94, (xiv)xe2x80x94NR13C(O)Oxe2x80x94or (xv) xe2x80x94OC(O)Oxe2x80x94, then A3 is not hydrogen,
(2) when  is a double bond and Y is hydrogen, then n is 1 or 2,
(3) when  is a single bond, Y is 
xe2x80x83n is 2,
m is 0 or 2, p is 0 or an integer of 1-4, ring A and ring B are benzene ring, R1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, then q is not 0,
(4) when  is a single bond, Y is 
xe2x80x83 n is 2,
m is 0 or 2, p is O or an integer of 1-4, ring A and ring B are benzene ring, R1 is C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen, and q is an integer of 1-5, then R2 is not C1-8 alkyl, C1-8 alkoxy, halogen, carboxy, nitro or C1-8 alkyl substituted with halogen,
(5) when xe2x80x83 is a double bond, Y is hydrogen, n is 2, p is 1 and ring A is benzene ring, then R1 is not halogen, C1-8 alkyl, phenylsulfonylamino, 2-methylphenylsulfonylamino, 3-methylphenylsulfonylamino, 4-methylphenylsulfonylamino, hydroxy, C1-8 alkoxy, nitro, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl,
(6) when xe2x80x83 is a double bond, Y is hydrogen, n is 2, p is 2 and ring A is benzene ring and one R1 is phenylsulfonylamino, 2-methylphenylsulfonylamino, 3-methylphenylsulfonylamino or 4-methylphenylsulfonylamino, then the other R1 is not C1-8 alkyl,
(7) when xe2x80x83 is a double bond, Y is hydrogen, n is 2, p is 2-3, ring A is benzene ring, one R1 is hydroxy, C1-8 alkoxy, or C1-8 alkoxy substituted with carboxy, hydroxy, C1-8 alkoxycarbonyl or hydroxyaminocarbonyl, then the other R1 is neither halogen nor C1-8 alkyl,
(8) when xe2x80x83 is a double bond, Y is hydrogen, n is 2, p is 3-4 and ring A is benzene ring, then two or three R1 are not t-butyl at the same time, and
(9) the following compounds (1)-(32) are excluded:
(1) 3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(2) 6-nitro-3-(thiophen-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(3) 3-(thiophen-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene,
(4) 4,5-dimethyl-1,1-dioxidebenzo[b]thiophene,
(5) 4,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
(6) 4,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
(7) 5,6-dimethyl-1,1-dioxidebenzo[b]thiophene,
(8) 5,7-dimethyl-1,1-dioxidebenzo[b[thiophene,
(9) 6,7-dimethyl-1,1-dioxidebenzo[b]thiophene,
(10) 4-carboxymethyl-1,1-dioxidebenzo[b]thiophene,
(11) 6-(2,2-bis(ethoxycarbonyl)ethenyl)amino-1,1-ioxidebenzo[b]thiophene,
(12) 4-methylaminocarbonyloxy-1,1-dioxidebenzo[b]thiophene,
(13) 5-(2-(N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamino)ethyl)-1,1-dioxidebenzo[b]thiophene,
(14) 5-(2-hydroxyethyl)-1,1-dioxidebenzo[b]thiophene,
(15) 5-bromo-7-methyl-1,1-dioxidebenzo[b]thiophene,
(16) 7-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
(17) 5-bromo-6-methyl-1,1-dioxidebenzo[b]thiophene,
(18) 5-bromo-4-methyl-1,1-dioxidebenzo[b]thiophene,
(19) 6-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
(20) 4-bromo-5-methyl-1,1-dioxidebenzo[b]thiophene,
(21) 6-amino-1,1-dioxidebenzo[b]thiophene,
(22) 6-acetylamino-1,1-dioxidebenzo[b]thiophene,
(23) 6-(4-diethylaminophenyl)-1,1-dioxidebenzo[b]thiophene,
(24) 1,1-dioxidethieno[2,3-b]pyridine,
(25) 1,1-dioxidethieno[3,2-b]pyridine,
(26) 1,1-dioxidethieno[2,3-c]pyridine,
(27) 5-amino-1,1-dioxidebenzo[b]thiophene,
(28) 5-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1,1-dioxidebenzo[b]thiophene,
(29) 4-(2-(1,1-dioxidebenzo[b]thiophen-3-yl)ethyl)-1,1dioxidebenzo[b]thiophene,
(30) 7-methyl-1,1-dioxidethieno[2,3-c]pyridine,
(31) 1,1-dioxidebenzo[b]thiophene or
(32) 4-(4-methoxyphenyl)-1,1-dioxidethieno[3,2-c]pyridine.], an N-oxide derivative thereof or a non-toxic salt thereof,
(3) a method for preparation of a fused thiophene derivative of the formula (IA), an N-oxide derivative thereof or a non-toxic salt thereof and
(4) a method for preparation of a compound of the formula (XI) 
which is characterized by cyanization of a compound of the formula (XII) 
to obtain a compound of the formula (XIII) 
then by subjecting to dehydration of the said compound of the formula (XIII) to obtain a compound of the formula (XIV) 
and then by subjecting to hydrolysis of the said compound of the formula (XIV).
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene group include straight or branched ones. In addition, isomers on double bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R-, S-, xcex1-, xcex2-isomer, enantiomer, diastereomer), optically active isomers (D-, L-, d-, I-isomer), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, mixtures thereof at voluntary ratios and racemic mixtures are also included in the present invention.
In the present invention, an N-oxide derivative of a compound of the formula (I) and (IA) means a compound wherein nitrogen atom(s) in a compound containing nitrogen atom(s) of the formula (I) and (IA) is (are) oxidized.
In the present invention, C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomers thereof.
C2-8 alkenyl means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, octatrienyl and the isomers thereof.
C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the isomers thereof.
C1-8 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and the isomers thereof.
C2-8 alkenylene means ethenylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene and the isomers thereof.
C2-8 alkynylene means ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octynylene and the isomers thereof.
Halogen means chloride, bromide, fluoride and iodide.
C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the isomers thereof.
Trihalomethyl means methyl substituted with three atoms selected from group consisting of chloride, bromide, fluoride and iodide atom.
Trihalomethoxyl means methoxyl substituted with three atoms selected from group consisting of chloride, bromide, fluoride and iodide atom.
C2-5 acyl means acetyl, propionyl, butyryl, valeryl and isomers thereof.
6-Membered monocyclic hetero aryl containing 1-2 nitrogen atom(s) includes, for example, pyridine, pyridine-N-oxide, pyrazine, pyrazine-N-monoxide, pyrazine-N-dioxide, pyrimizine, pyrimizine-N-monoxide, pyrimizine-N-dioxide, pyridazine, pyridazine-N-monoxide, pyridazine-N-dioxide ring etc.
C3-15 Mono-, bi- or tricyclic carbo ring includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopenten, cyclohexen, cyclopentadien, cyclohexadien, benzene, penthalene, indene, naphthalene, azulene, florene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydropentalene, perhydroindene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, perhydrobiphenylene ring etc.
4-18 Membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom includes 4-18 membered mono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom or corresponding hetero ring in which ring is saturated partially or fully.
The said 4-18 membered mono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom includes, for example, pyrrole, pyrrole-N-oxide, imidazole, triazole, tetrazole, pyrazole, pyridine, pyridine-N-oxide, pyrazine, pyrazine-N-monoxide, pyrazine-N-dioxide, pyrimizine, pyrimizine-N-monoxide, pyrimizine-N-dioxide, pyridazine, pyridazine-N-monoxide, pyridazine-N-dioxide, azepine, diazepine, furan, pyran, oxepine, oxazepine, thiophene, thiain (thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, quinoline-N-oxide, isoquinoline, isoquinoline-N-oxide, phthalazine, naphthyridine, naphthyridine-N-monoxide, naphthyridine-N-dioxide, quinoxaline, quinoxaline-N-monoxide, quinoxaline-N-dioxide, quinazoline, quinazoline-N-monoxide, quinazoline-N-dioxide, cinnoline, benzoxazole, benzothiazole, benzoimidazole, carbazole, acridine ring etc.
The said 4-18 membered mono-, bi- or tricyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or one sulfur atom in which ring is saturated partially or fully includes, for example, pyrroline, pyrrolidine, pyrrolidine-N-oxide, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, dihydropyridine, dihydropyridine-N-oxide, dihydropyrazine, dihydropyrazine-N-monoxide, dihydropyrazine-N-dioxide, dihydropyrimizine, dihydropyrimizine-N-monoxide, dihydropyrimizine-N-dioxide, dihydropyridazine, dihydropyridazine-N-monoxide, dihydropyridazine-N-dioxide, piperidine, piperidine-N-oxide, piperazine, piperazine-N-monoxide, piperazine-N-dioxide, tetrahydropyrimizine, tetrahydropyrimizine-N-monoxide, tetrahydropyrimizine-N-dioxide, tetrahydropyridazine, tetrahydropyridazine-N-monoxide, tetrahydropyridazine-N-dioxide, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran), dihydroxazole, tetrahydroxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, morpholine-N-oxide, thiomorpholine, thiomorpholine-N-oxide, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, dihydroquinoline-N-oxide, tetrahydroquinoline, tetrahydroquinoline-N-oxide, perhydroquinoline, perhydroquinoline-N-oxide, dihydroisoquinoline, dihydroisoquinoline-N-oxide, tetrahydroisoquinoline, tetrahydroisoquinoline-N-oxide, perhydroisoquinoline, perhydroisoquinoline-N-oxide, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, dihydronaphthyridine-N-monoxide, dihydronaphthyridine-N-dioxide, tetrahydronaphthyridine, tetrahydronaphthyridine-N-monoxide, tetrahydronaphthyridine-N-dioxide, perhydronaphthyridine, perhydronaphthyridine-N-monoxide, perhydronaphthyridine-N-dioxide, dihydroquinoxaline, dihydroquinoxaline-N-monoxide, dihydroquinoxaline-N-dioxide, tetrahydroquinoxaline, tetrahydroquinoxaline-N-monoxide, tetrahydroquinoxaline-N-dioxide, perhydroquinoxaline, perhydroquinoxaline-N-monoxide, perhydroquinoxaline-N-dioxide, dihydroquinazoline, dihydroquinazoline-N-monoxide, dihydroquinazoline-N-dioxide, tetrahydroquinazoline, tetrahydroquinazoline-N-monoxide, tetrahydroquinazoline-N-dioxide, perhydroquinazoline, perhydroquinazoline-N-monoxide, perhydroquinazoline-N-dioxide, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzoazepine, benzodiazepine, indroxoazepine, indrotetrahydroxazepine, indroxadiazepine, indrotetrahydroxadiazepine, indrothiazepine, indrotetrahydrothiazepine, indrothiadiazepine, indrotetrahydrothiadiazepine, indroazepine, indrotetrahydroazepine, indrodiazepine, indrotetrahydrodiazepine, benzofurazane, benzothiadiazole, benzotriazole, camphar, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, 1,3-dioxaindan, 1,4-dioxoindan ring etc.
In the present invention, m is, preferably, 0 or 2 and most preferably, 2.
n is, preferably, 0 or 2 and most preferably, 2.
p is, preferably, 1 or 2 and most preferably, 2.
q is, preferably, 0 or 1.
Z is, preferably, single bond or C1-8 alkylene, and most preferably, single bond. 
xe2x80x83is, preferably, pyridine or benzene ring, and most preferably, benzene ring. 
xe2x80x83is, preferably, C5-10 mono- or bicyclic carbo ring or 5-10 membered mono- or bicyclic hetero ring containing 1-3 nitrogen atom(s), one oxygen atom and/or one sulfur atom, more preferably, benzene, cyclohexane, thiophene, furan, pyridine, pyrimizine, imidazole ring, and most preferably, benzene or thiophene ring.
R1 is, preferably, C1-8 alkyl, nitro, cyano, halogen, Cyc1 or C1-8 alkyl substituted with halogen or Cyc1, or A1xe2x80x94A2xe2x80x94A3, and most preferably, C1-8 alkyl substituted with Cyc1 or A1xe2x80x94A2xe2x80x94A1.
A1 is, preferably, single bond, C1-8 alkylene, C2-8 alkenylene, and most preferably, single bond or C1-8 alkylene.
A2 is, preferably, xe2x80x94Oxe2x80x94, xe2x80x94NR3xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR4xe2x80x94, xe2x80x94NR5C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94NR13C(O)Oxe2x80x94, and most preferably, Oxe2x80x94, xe2x80x94NR3xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR4xe2x80x94, xe2x80x94NR5C(O)xe2x80x94.
A3 is, preferably, C1-8 alkyl, Cyc1, or C1-8 alkyl or C2-8 alkenyl substituted with Cyc1, xe2x80x94C(O)R17, xe2x80x94NR19R20 or xe2x80x94OR18, and most preferably, C1-8 alkyl substituted with Cyc1 or NR19R20.
Cyc1 is, preferably, C5-10 mono- or bicyclic carbo ring or 5-10 membered mono- or bicyclic hetero ring containing 1-3 nitrogen atom(s), one oxygen atom and/or one sulfur atom, and more preferably, C5-10 monocyclic carbo ring or 5-10 membered monocyclic hetero ring containing 1-2 nitrogen atom(s) and/or one oxygen atom, and most preferably, benzene, piperidine, piperazine, pyrrolidine, pyridine or morpholine ring.
R19, R20 is, preferably, hydrogen or C1-8 alkyl, and most preferably, methyl, ethyl, propyl or isopropyl.
[Salts]
In the present invention, non-toxic salts include all such salts, for example, ordinal salts, acid-addition salts and hydrate salts.
The compounds of the present invention of the formula (I) may be converted into the corresponding salts by known method. Non toxic and water-soluble salts are preferable. Suitable salts include the salts of alkalimetal (sodium, potassium etc.), alkaline-earth metal (calcium, magnesium etc.), ammonium salts, salts of organic amine which is pharmaceutically permitted (tetramethyl ammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenetylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-gulcamine etc.).
The compounds of the present invention of the formula (I) may be converted into the corresponding acid-addition salts by known method. Non toxic and water-soluble acid-addition are preferable. Suitable acid-addition salts include the salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfonic acid, phosphonic acid, nitric acid and the salts with organic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid.
The compounds of the present invention of the formula (I) or salts thereof may be converted into a corresponding hydrate by known methods.
In the compounds of the formula (I), preferred compounds are as follows: the compound of the formula (I-A) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-B) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-C) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-D) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-E) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-F) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-G) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-H) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-J) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-K) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-L) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-M) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-N) 
(wherein all the symbols are the same meanings as hereinbefore described.), the compound of the formula (I-O) 
(wherein all the symbols are the same meanings as hereinbefore described.), or the compound of the formula (I-P) 
(wherein all the symbols are the same meanings as hereinbefore described.).
In the compounds of the formula (I-A), the compound of the formula (I-Axe2x80x2) 
(wherein, R1xe2x80x2 is C1-8 alkyl substituted with Cyc1, or
xe2x80x94A1xe2x80x2xe2x80x94A2xe2x80x2xe2x80x94A3 
(wherein, A1xe2x80x2 is single bond or C1-8 alkylene, A2xe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94NR3xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NR4xe2x80x94 or NR5C(O)xe2x80x94 and the other symbols are the same meanings as hereinbefore described.) and the other symbols are the same meanings as hereinbefore described.) is most preferable.
In the compound of the formula (I-N), the compound of the formula (I-Nxe2x80x2) 
(wherein all the symbols are the same meanings as hereinbefore described.) is most preferable.
The following compounds (1)-(4) are known and marketed ones, but their activities as inhibitor of producing IL-6 and/or IL-12 have not been known at all. The compounds (1)-(4) and non-toxic salts thereof are also preferable ones used in the present invention.
For example,
Compound (1): 3-(thiophene-2-yl)sulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08156). 
Compound (2): 6-nitro-3-(thiophene-2-yl)thio-2,3-dihydro-1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08165): 
Compound (3): 3-(thiophene-2-yl)thio-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08138): 
Compound (4): 3-phenylsulfonyl-2,3-dihydro-1,1-dioxidebenzo[b]thiophene (Maybridge, Catalog No. KM 08140): 
More preferable compounds are the following known compounds and the compounds shown in the Tables 1 to 78 and described in Examples and non-toxic salts thereof.
In the following tables, 3-Py is pyridin-3-yl, Me is methyl, Et is ethyl, n-Pr is normalpropyl, i-Pr is isopropyl, t-Bu is t-butyl and the other symbols are the same meanings as hereinbefore described.
[Methods for Preparation of the Compounds of the Present Invention]
The compounds of the present invention of the formula (I) of the present invention may be prepared by the following methods or the methods described in examples.
Among the compounds of the present invention of the formula (I), the compounds of the present invention of the formula (I-1) 
(wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by the known methods or the following methods [1]xcx9c[14].
[1] The compounds of the present invention of the formula (I-1) in which n is 1 or 2 may be also prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-1) in which n is 1, i.e., the compounds of the present invention of the formula (I-1-1a) 
(wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidation of the compounds of the formula (I-1-1c) 
(wherein all the symbols are the same meanings as hereinbefore described.)
The above oxidation is known per se. For example, it may be carried out in an adequate organic solvent (e.g., methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.), in the presence of an 1-1.2 equivalent amount of oxidizing agent (e.g., hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., 3-chloroperbenzoic acid, peracetic acid etc.), potassium peroxymonosulfate, potassium permanganate, chromic acid etc.), at xe2x88x9240xc2x0 C.xcx9c0xc2x0 C.
(b) The compounds of the present invention of the formula (I-1) in which n is 2, i.e., the compounds of the present invention of the formula (I-1-1b) 
(wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidation of the said the compounds of the formula (I-1-1c).
The above oxidation is known per se. For example, it may be carried out in an adequate organic solvent (e.g., methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.), in the presence of an excess amount of oxidizing agent (e.g., hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, peracid (e.g., 3-chloroperbenzoic acid, peracetic acid etc.), potassium peroxymonosulfate, potassium permanganate, chromic acid etc.), at 20xc2x0 C.xcx9c60xc2x0 C.
[2] The compounds of the present invention of the formula (I-1) in which at least one of R1 (s) is a substituted oxy group or a group containing substituted oxy, i.e., the compounds of the present invention of the formula (I-1-2) 
(wherein, R1-1-2 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-2 (s) is a substituted oxy group or a group containing substituted oxy and the other symbols are the same meaning as hereinbefore described.) may be also prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-1-2) may be prepared by etherification of the compounds of the formula (I-1-2) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-2a) 
(wherein, R1-1-2a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-2a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing a group which is removal (chloride, bromide, iodide, mesyl or tosyl etc.).
This etherification is well known. For example, it may be carried out in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of hydroxide of an alkalimetal (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or carbonate (sodium carbonate , potassium carbonate etc.) or an aqueous solution thereof or a mixture thereof at 0xcx9c100xc2x0 C.
(b) The compounds of the present invention of the formula (I-1-2) may be prepared by etherification of the compounds of the formula (I-1-2) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-2b) 
(wherein, R1-1-2b is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-2b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing hydroxy.
This etherification is well known. For example, it may be carried out in an organic solvent (methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene etc.) in the presence of azo compounds (diethyl azodicaroxylate, diisopropyl azodicaroxylate, 1,1xe2x80x2-(azodicarbonyl)dipiperidine, 1,1xe2x80x2-azobis(N,N-dimethylformamide) etc.) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine etc.), with the corresponding alcohol compounds at 0xcx9c60xc2x0 C.
[3] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted amino or a group containing substituted amino, i.e., the compounds of the present invention of the formula (I-1-3) 
(wherein, R1-1-3 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-3(s) is a substituted amino or a group containing substituted amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)xcx9c(d).
(a) The compounds of the present invention of the formula (I-1-3) may be prepared by reacting the compounds of the formula (I-1-3) in which at least one of R1(s) is halogen (chloride, bromide, iodide) or a group containing halogen, i.e., the compounds of the formula (I-1-3a) 
(wherein, R1-1-3a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-3a(s) is a halogen (chloride, bromide, iodide) or a group containing halogen and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
This reaction is well known. For example, it may be carried out in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran, acetonitrile etc.) in the presence or absence of base (triethylamine, pyridine etc.) at 0xcx9c100xc2x0 C.
(b) The compounds of the present invention of the formula (I-1-3) may be prepared by reacting the compounds of the formula (I-1-3) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-3b) 
(wherein, R1-1-3b is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-3b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing halogen (chloride, bromide, and iodide).
This reaction may be carried out by the same procedure for the preparation of the said compounds of the formula (I-1-3a).
(c) The compounds of the present invention of the formula (I-1-3) may be prepared by reductive amidation of the compounds of the formula (I-1-3) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-3c) 
(wherein, R1-1-3c is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-3c(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing carbonyl.
This reductive amidation is well known. For example, it may be carried out in an organic solvent (methanol, ethanol, dimethylformamide, dimethylsulfoxide etc.) in the presence of reductant (sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, Pd-C etc.) and in the presence of acid (acetic acid, hydrochlolride solution etc.), if necessary, at xe2x88x9220xcx9c60xc2x0 C.
(d) The compounds of the present invention of the formula (I-1-3) may be prepared by reductive amidation of the compounds of the formula (I-1-3) in which at least one of R1(s) is a carbonyl or a group containing carbonyl, i.e., the compounds of the formula (I-1-3d) 
(wherein, R1-1-3d is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-3d(s) is a carbonyl or a group containing carbonyl and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing amino.
This reductive amidation may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-3c).
[4] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is an amide or a group containing amide, i.e., the compounds of the present invention of the formula (I-1-4) 
(wherein, R1-1-4 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-4(s) is an amide or a group containing amide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-1-4) may be prepared by amidation of the compounds of the formula (I-1) in which at least one of R1(s) is a xe2x80x94COOH or a group containing xe2x80x94COOH, i.e., the compounds of the formula (I-1-4a) 
(wherein, R1-1-4is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-4a(s) is a xe2x80x94COOH or a group containing xe2x80x94COOH and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing amino.
The amidation is well known. For example, it may be carried out
(1) by the method with using acid halide,
(2) by the method with using mixed acid anhydride,
(3) by the method with using conducing agent etc.
Concrete description of these methods are as follows:
(1) method with using acid halide may be carried out, for example; carboxylic acid is reacted with an acid halide (oxalyl chloride or thionyl chloride etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) or without solvents at from xe2x88x9220xc2x0 C. to a refluxing temperature to give an acid halide. The obtained acid halide and an amine are reacted in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0-40xc2x0 C.
(2) method with using mixed acid anhydride may be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran. etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.), at 0-40xc2x0 C.
(3) method with using condensing agent may be carried out, for example; a carboxylic acid and an amine are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran. etc.) or without solvents in the presence or absence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) using with condensing agent (1,3-dicyclohexylcarbodiimido (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 1,1xe2x80x2-carbonydiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, propane phosphate cyclic anhydride etc.) using or without 1-hydroxybenztriazole (HOBt) at 0-40xc2x0 C. (etc.)
Preferably, the above reactions (1), (2) and (3) described above are carried out under an atmosphere of an inert gas (argon, nitrogen etc.) on anhydrous condition.
(b) The compounds of the present invention of the formula (I-1-4) may be prepared by amidation of the compounds of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-4b) 
(wherein, R1-1-4b is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-4b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing carboxy.
The above amidation may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-4a).
[5] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is an ester or a group containing ester, i.e., the compounds of the present invention of the formula (I-1-5) 
(wherein, R1-1-5 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-5(s) is an ester or a group containing ester and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-1-5) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R1(s) is a xe2x80x94COOH or a group containing xe2x80x94COOH, i.e., the compounds of the formula (I-1-5a) 
(wherein, R1-1-5a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-5a(s) is a xe2x80x94COOH or a group containing xe2x80x94COOH and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing hydroxy.
Esterification is well known. For example, it may be carried out
(1) by the method with using acid halide,
(2) by the method with using mixed acid anhydride,
(3) by the method with using conducing agent etc.
Concrete description of the above methods are as follows:
(1) method with using acid halide may be carried out, for example; carboxylic acid is reacted with an acid halide (oxalyl chloride or thionyl chloride etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) or without solvents at from xe2x88x9220xc2x0 C. to a refluxing temperature to give an acid halide. The obtained acid halide and an alcohol are reacted in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) at 0-40xc2x0 C.
(2) method with using mixed acid anhydride may be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride etc.) or an acid derivative (ethyl chloroformate, isobutyl chloroformate etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran. etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.), at 0-40xc2x0 C. to give an acid halide. The obtained acid halide and an alcohol are reacted in an inert organic solvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran etc.) at 0-40xc2x0 C.
(3) method with using condensing agent may be carried out, for example; a carboxylic acid and an alcohol are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran. etc.) or without solvents in the presence or absence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) using with condensing agent (1,3-dicyclohexylcarbodiimido (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 1,1xe2x80x2-carbonydiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, propane phosphate cyclic anhydride etc.) using or without 1-hydroxybenztriazole (HOBt) at 0-40xc2x0 C.
Preferably, the reactions (1), (2) and (3) described above are carried out under an atmosphere of inert gas (argon, nitrogen etc.) on anhydrous condition.
(b) The compounds of the present invention of the formula (I-1-5) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-5b) 
(wherein, R1-1-5b is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-5b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing carboxy.
The esterification may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-5a).
[6] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a sulfonamide or a group containing sulfonamide, i.e., the compounds of the present invention of the formula (I-1-6) 
(wherein, R1-1-6 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-6(S) is a sulfonamide or a group containing sulfonamide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-1-6) may be prepared by sulfonamidation of the compounds of the formula (I-1) in which at least one of R1(s) is a xe2x80x94SO3H or a group containing xe2x80x94SO3H, i.e., the compounds of the formula (II) 
(wherein, R1-1-6a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-6a(s) is a xe2x80x94SO3H or a group containing xe2x80x94SO3H and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing amino.
The sulfonamidation is well known. For example, it may be carried out by reacting sulfonic acid with acid halide (oxazolyl chloride, thionyl chloride etc.) in an inert organic solvent (chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) or without solvent, at xe2x88x9220xc2x0 C.xcx9crefluxing temperature to obtain sulfonylhalide and then by reacting the obtained sulfonylhalide with an amine in an inert organic solvent (chloroform, methyhlene chloride, diethyl ether, tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) at 0xcx9c40xc2x0 C.
(b) The compounds of the present invention of the formula (I-1-6) may be prepared by sulfonamidation of the compounds of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-6b) 
(wherein, R1-1-6b is the same meanings as hereinbefore described for -R1, provided that at least one of R1-1-6b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing sulfo.
The sulfonamidation may be carried out the same procedure for preparation of the said compounds of the formula (I-1-6a).
[7] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy, i.e., the compounds of the present invention of the formula (I-1-7) 
(wherein, R1-1-7 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-7(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-1) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-7a) 
(wherein, R1-1-7a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-7a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing isocyanate.
This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, methyhlene chloride, diethyl ether etc.) in the presence of base (1,8-diazabicyclo[5.4.0]undec-7-en (DBU), triethylamine, sodium hydride etc.) at 0xcx9c100xc2x0 C.
[8] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted aminocarbonylamino or a group containing a substituted aminocarbonylamino, i.e., the compounds of the present invention of the formula (I-1-8) 
(wherein, R1-1-8 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-8(s) is a substituted aminocarbonyl or a group containing a substituted aminocarbonyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-8a) 
(wherein, R1-1-8a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-8a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding compounds containing isocyanate.
This reaction may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-7).
[9] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino, i.e., the compounds of the present invention of the formula (I-1-9) 
(wherein, R1-1-9 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-9(s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino and the other symbols are the same meaning as hereinbefore described.) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-1-9a) 
(wherein, R1-1-9a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-9a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) with the corresponding halo formic acid ester.
This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, methyhlene chloride, diethyl ether etc.) in the presence of base (triethylamine, pyridine etc.) at xe2x88x9278xcx9c40xc2x0 C.
[10] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy, i.e., the compounds of the present invention of the formula (I-1-10) 
(wherein, R1-1-10 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-10(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by esterification of the compounds of the formula (I-1) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-1-10a) 
(wherein, R1-1-10a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-10a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with the corresponding halo formic acid ester.
This reaction may be carried out by the same procedure for preparation of the said compounds of the formula (I-1-9).
[11] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl, i.e., the compounds of the present invention of the formula (I-1-11) 
(wherein, R1-1-11 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-11(s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-1-11) in which n is 0, i.e., the compounds of the present invention of the formula (I-1-11a) 
(wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-1) in which at least one of R1(s) is a formyl i.e., the compounds of the formula (I-1-11 aa) 
(wherein, R1-1-11a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-11a(s) is a formyl and the other symbols are the same meaning as hereinbefore described.) with the corresponding Grignard""s reagents or corresponding derivatives containing lithium.
This reaction is well known. For example, it may be carried out in an organic solvent (tetrahydrofuran, diethyl ether etc.) at xe2x88x9278xcx9c0xc2x0 C.
(b) The compounds of the present invention of the formula (I-1-11) in which n is 1 or 2, i.e., the compounds of the present invention of the formula (I-1-11b) 
(wherein, n-1-11b is an integer of 1xcx9c2 and the other symbols are the same meaning as hereinbefore described.) may be prepared by oxidizing the said compounds of the formula (I-1-11a) as described in [1].
[12] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a substituted carbonyl or a group containing substituted carbonyformyl, i.e., the compounds of the present invention of the a formula (I-1-12) 
(wherein, R1-1-12 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-12(s) is an substituted carbonyl or a group containing substituted carbonyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by oxidizing the said compounds of the formula (I-1-11).
This oxidation is well known. For example, it may be carried out in an organic solvent (methyhlene chloride, chloroform etc.) using oxidant (manganese dioxide, oxazolyl chloride, pyridinium dichromate etc.) at xe2x88x9278xcx9c40xc2x0 C.
[13] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is an amino or a group containing amino, i.e., the compounds of the present invention of the formula (I-1-13) 
(wherein, R1-1-13 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-13(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reducing nitro in the compounds of the formula of (I-1) in which at least one of R1(s) is a nitro or a group containing nitro, i.e., the compounds of the formula (I-1-13a) 
(wherein, R1-1-13a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-13a(s) is a nitro or a group containing nitro and the other symbols are the same meaning as hereinbefore described.).
The reduction of nitro is well known. For example, it may be carried out by hydrogenolysis and reduction using organic metal.
This hydrogenolysis is well known. For example, it may be carried out in inert solvent [ethers (e.g., tetrahydrofuran, dioxane, dimethoxy ethane, diethyl ether etc.), alcohols (e.g., methanol , ethanol etc.), benzenes (e.g., benzene, toluene etc.), ketones (e.g., acetone, methyl ethyl ketone etc.), nitrites (e.g., acetonitrile etc.), amides (e.g., dimethylformamide etc.), water, ethyl acetate, acetic acid or mixture of the said two or more solvents etc.], in the presence of catalyst to hydrogenate (e.g., Pdxe2x80x94C, palladium black, Pd, palladium hydroxide, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.), in the presence or absence of an inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid etc.) or an organic acid (e.g., acetic acid, p-toluenesulfonic acid, bromic acid, trifluoroacetic acid, formic acid etc.), at an ordinary or increased pressure under an atmosphere of hydrogen gas or in the presence of ammonium formate at 0xcx9c200xc2x0 C. When an acid is used, its salt may be used.
The reduction using an organic metal is well known. For example, it may be carried out in a water-admissible solvent (ethanol , methanol etc.) in the presence or absence of an aqueous hydrochloric acid solution, using an organic metal (Zn, Fe, Sn, SnCl2, FeCl2 etc.) at 50xcx9c150xc2x0 C.
[14] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) is a xe2x80x94COOH, hydroxy or amino or a group containing xe2x80x94COOH, hydroxy or amino, i.e., the compounds of the present invention of the formula (I-1-14) 
(wherein, R1-1-14 is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-14(s) is a xe2x80x94COOH, hydroxy or amino or a group containing xe2x80x94COOH, hydroxy or amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by removal of protecting group in the compounds of the formula (I-1) containing a protected COOH, hydroxy or amino, i.e., the compounds of the formula (I-1-14a) 
(wherein, R1-1-14a is the same meanings as hereinbefore described for R1, provided that at least one of R1-1-14a(s) is a protected COOH (e.g., it is protected by methyl, ethyl, t-butyl and benzyl etc.), protected hydroxy (e.g., it is protected by methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl etc.) or protected amino (e.g., it is protected by benzyloxycarbonyl, t-butoxycarbonyloxy, trifluoroacetyl etc.) or a group containing such a group, and the other symbols are the same meaning as hereinbefore described.) according to alkaline hydrolysis, removal of protecting group in an acidic condition, removal of silyl or hydrogenolysis.
The removal of a protecting group according to alkaline hydrolysis is well known. For example, it may be carried out in an organic solvent (methanol, tetrahydrofuran, dioxane etc.), using hydroxide of an alkaline metal (sodium hydroxide, potassium hydroxide , lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or carbonate (sodium carbonate, potassium carbonate etc.) or an aqueous solution thereof or a mixture thereof at 0xcx9c40xc2x0 C.
The removal of a protecting group in an acidic condition is well known. For example, it may be carried out in an organic solvent (methyhlene chloride, chloroform, dioxane, ethyl acetate, anisole etc.), organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, trimethylsilyliodide etc.) or inorganic acid (hydrochloric acid, sulfuric acid etc.) or a mixture thereof (bromohydroacetic acid etc.) at 0xcx9c100xc2x0 C.
The removal of silyl is well known. For example, it may be carried out in a water-admissible organic solvent (tetrahydrofuran, acetonitrile etc.), using tetrabutylammonium fluoride at 0xcx9c40xc2x0 C.
The removal of protecting group according to hydrogenolysis may be carried out by the same procedure of hydrogenolysis described in [13].
Among the compounds of the formula (I), the compounds of the formula (I-2) 
may be prepared by the following methods [15]xcx9c[17].
[15] The compounds of the present invention of the formula (I-2) in which m is 0, i.e., the compounds of the present invention of the formula (I-2-15) 
(wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-2-15) in which n is 1 or 2, i.e., the compounds of the present invention of the formula (I-2-15a) 
(wherein, n-2-15a is an integer of 1xcx9c2 and the other symbols are the same meanings as hereinbefore described.) may be prepared by reacting the said compounds of the formula (I-1-1a) or the compounds of the formula (I-1-1b) and the compounds of the formula (III) 
(wherein all the symbols are the same meanings as hereinbefore described.).
This reaction is known one (to see J. Am. Chem. Soc., 72, 1985 (1950), J. Org. Chem., 54, 4232 (1989). For example, it may be carried out in an inert organic solvent (tetrahydrofuran, diethyl ether, methylene chloride, chloroform, benzene, toluene, dimethylformamide, dimethylsulfoxide, acetonitrile etc.) using hydride of an alkaline metal, hydroxide of an alkaline metal (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), hydroxide of an alkaline earth metal (barium hydroxide, calcium hydroxide etc.) or tertiary amine (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.) or an aqueous solution thereof, or a mixture thereof at 0xcx9c40xc2x0 C.
(b) The compounds of the present invention of the formula (I-2-15) in which n is 0, i.e., the compounds of the present invention of the formula (I-2-15b) 
(wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by reduction of the compounds obtained by the above mentioned method in which m is 0, n is 1, i.e., the compounds of the formula (I-2-15ab) 
(wherein all the symbols are the same meanings as hereinbefore described.).
This reduction reaction is well known. For example, this reaction may be carried out in an organic solvent (diethyl ether, tetrahydrofuran etc.) using reductant (lithium aluminum hydride, aluminum diisobutylhydride etc.) at 0xcx9c80xc2x0 C.
[16] The compounds of the present invention of the formula (I-2) in which m is 1, i.e., the compounds of the present invention of the formula (I-2-16) 
(wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidizing the said compounds of the formula (I-2-15).
This oxidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-1a) in [1].
[17] The compounds of the present invention of the formula (I-2) in which m is 2, i.e., the compounds of the present invention of the formula (I-2-17) 
(wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by the following methods (a)xcx9c(c).
(a) The compounds of the present invention of the formula (I-2-17) in which n is 1 or 2, i.e., the compounds of the present invention of the formula (I-2-17a) 
(wherein, n-2-17a is an integer of 1xcx9c2 and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the said compounds of the formula (I-1-1a) or the compounds of the formula (I-1-1b) and the compounds of the formula (IV) 
(wherein all the symbols are the same meanings as hereinbefore described.).
This reaction may be carried out by the same procedure described in the reaction of the compounds of the formula (I-2-15a) and the compounds of the formula (III) in [15].
(b) The compounds of the present invention of the formula (I-2-17) in which n is 0, i.e., the compounds of the formula (I-2-17b) 
(wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by reduction of the compounds of the formula (V) 
(wherein all the symbols are the same meanings as hereinbefore described.).
This reduction is known one. For example, it may be carried out by hydrogenation or by the method using triethylsilane.
This hydrogenation is known reaction. For example, it may be carried out in inert solvent [ethers (e.g., tetrahydrofuran, dioxane, dimethoxy ethane, diethyl ether etc.), alcohols (e.g., methanol, ethanol etc.), benzenes (e.g., benzene, toluene etc.), ketones (e.g., acetone, methyl ethyl ketone etc.), nitriles (e.g., acetonitrile etc.), amides (e.g., dimethylformamide etc.), water, ethyl acetate, acetic acid or mixture of the said two or more solvents etc.], in the presence of catalyst to hydrogenate (e.g., Pdxe2x80x94C, palladium black, Pd, palladium hydroxide, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.), in the presence or absence of an inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid etc.) or an organic acid (e.g., acetic acid, p-toluenesulfonic acid, bromic acid, trifluoroacetic acid, formic acid etc.), at an ordinary or increased pressure under an atmosphere of hydrogen gas, or in the presence of ammonium formate at 0xcx9c200xc2x0 C. When an acid is used, its salt may be used.
This reduction using triethylsilane is well known. For example, it may be carried out in trifluoroacetic acid, in the presence of triethylsilane at 0xcx9c100xc2x0 C.
(c) The compounds of the present invention of the formula (I-2-17) in which n is 2, i.e., the compounds of the present invention of the formula (I-2-17c) 
(wherein all the symbols are the same meanings as hereinbefore described.) may be prepared by oxidizing the compounds obtained by the above mentioned method in which m is 0 and n is 2, i.e., the compounds of the formula (I-2-15ac) 
(wherein all the symbols are the same meanings as hereinbefore described.).
This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-1b) in [1].
The compounds of the present invention of the formula (I-2) may be also prepared by not only the methods described in [15]xcx9c[17] but also the following methods [18]xcx9c[30].
[18] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted oxy or a group containing substituted oxy, i.e., the compounds of the present invention of the formula (I-2-18) 
(wherein, R1-2-18 and R2-2-18 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-18(s) and R2-2-18(s) is a substituted oxy or a group containing substituted oxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-2-18) may be prepared by eterification of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-18a) 
(wherein, R1-2-18a and R2-2-8a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-18a(s) and R2-2-18a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing a group which is removal (chloride, bromide, iodide, mesyl or tosyl etc.).
This eterification may be carried out by the same procedure for preparation of the compounds of the formula (I-1-2a) in [2].
(b) The compounds of the present invention of the formula (I-2-18) may be prepared by eterification of the compounds of the formula (I-2) in which at least one of R1(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-18b) 
(wherein, R1-2-18b and R2-2-18b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-18b(s) and R2-2-18b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) with corresponding compounds containing hydroxy.
This eterification may be carried out by the procedure for preparation of the compounds of the formula (I-1-2b) in [2].
[19] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted amino or a group containing substituted amino, i.e., the compounds of the present invention of the formula (I-2-19) 
(wherein, R1-2-19 and R2-2-19 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19(s) and R2-2-19(s) is a substituted amino or a group containing substituted amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)xcx9c(d).
(a) The compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a halogen (chloride, bromide, iodide) or a group containing halogen, i.e., the compounds of the formula (I-2-19a) 
(wherein, R1-2-19a and R2-2-19a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19a(s) and R2-2-19a(s) is a halogen (chloride, bromide, iodide) or a group containing halogen and the other symbols are the same meaning as hereinbefore described.) and the compounds containing amino.
This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3a) in [3].
(b) The compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-19b) 
(wherein, R1-2-19b and R2-2-19b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19b(s) and R2-2-19b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing halogen (chloride, bromide, and iodide).
This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3a) in [3].
(c) The compounds of the present invention of the formula (I-2-19) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-19c) 
(wherein, R1-2-19c and R2-2-19c are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19c(s) and R2-2-19c(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carbonyl.
This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3c) in [3].
(d) The compounds of the present invention of the formula (I-2-19) may be prepared by reductive amidation of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a carbonyl or a group containing carbonyl, i.e., the compounds of the formula (I-2-19d) 
(wherein, R1-21-9d and R2-2-19d are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-19d(s) and R2-2-19d(s) is a carbonyl or a group containing carbonyl and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
This reductive amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-3c) in [3].
[20] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is an amide or a group containing amide, i.e., the compounds of the present invention of the formula (I-2-20) 
(wherein, R1-2-20 and R2-2-20 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-20(s) and R2-2-20(s) is an amide or a group containing amide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-2-20) may be prepared by amidation of the compounds of the formula (I-2) in which at least one of at least one of R1(s) or R2(s) is a xe2x80x94COOH or a group containing xe2x80x94COOH, i.e., the compounds of the formula (I-2-20a) 
(wherein, R1-2-20a and R2-2-20a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-20a(s) and R2-2-20a(s) is a xe2x80x94COOH or a group containing-COOH and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
The amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-4) in [4].
(b) The compounds of the present invention of the formula (I-2-20) may be prepared by amidation of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-20b) 
(wherein, R1-2-20b and R2-2-20b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-20b(s) and R2-2-20b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carboxy.
The amidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-4) in [4].
[21] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is an ester or a group containing ester, i.e., the compounds of the present invention of the formula (I-2-21) 
(wherein, R1-2-21 and R2-2-21 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-21(s) and R2-2-21(s) is an ester or a group containing ester and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-2-21) may be prepared by esterification of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a xe2x80x94COOH or a group containing xe2x80x94COOH, i.e., the compounds of the formula (I-2-21a) 
(wherein, R1-2-21a and R2-2-21a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-21a(s) and R2-2-21a(s) is a xe2x80x94COOH or a group containing xe2x80x94COOH and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing hydroxy.
This esterification may be carried out by the same procedure for preparation of the compounds of the formula (I-1-5) in [5].
(b) The compounds of the present invention of the formula (I-2-21) may be prepared by esterification of the compounds of the formula (I-2) in which R1(s) or R2(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-21b) 
(wherein, R1-2-21b and R2-2-21b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-21b(s) and R2-2-21b(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing carboxy.
This esterification may be carried out by the same procedure for preparation of the compounds of the formula (I-1-5) in [5].
[22] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a sulfonamide or a group containing sulfonamide, i.e., the compounds of the present invention of the formula (I-2-22) 
(wherein, R1-2-22 and R2-2-22 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-22(s) and R2-2-22(s) is a sulfonamide or a group containing sulfonamide and the other symbols are the same meaning as hereinbefore described.) may be prepared by the following methods (a)xcx9c(b).
(a) The compounds of the present invention of the formula (I-2-22) may be prepared by sulfonamidation of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a xe2x80x94SO3H or a group containing xe2x80x94SO3H, i.e., the compounds of the formula (VI) 
(wherein, R1-2-22a and R2-2-22a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-22a(s) and R2-2-22a(s) is a xe2x80x94SO3H or a group containing xe2x80x94SO3H and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing amino.
The sulfonamidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-6a) in [6].
(b) The compounds of the present invention of the formula (I-2-22) may be prepared by sulfonamidation of the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-22b) 
(wherein, R1-2-22b and R2-2-22b are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-22b(s) and R2-2-22b(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing sulfo.
The sulfonamidation may be carried out by the same procedure for preparation of the compounds of the formula (I-1-6a) in [6].
[23] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy, i.e., the compounds of the present invention of the formula (I-2-23) 
(wherein, R1-2-23 and R2-2-23 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-23(s) and R2-2-23(s) is a substituted aminocarbonyloxy or a group containing a substituted aminocarbonyloxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-23a) 
(wherein, R1-2-23a and R2-2-23a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-23a(s) and R2-2-23a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing isocyanate.
This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-7) in [7].
[24] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted aminocarbonylamino or a group containing a substituted aminocarbonylamino, i.e., the compounds of the present invention of the formula (I-2-24) 
(wherein, R1-2-24 and R2-2-24 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-24(s) and R2-2-24(s) is a substituted aminocarbonylamino or a group containing a substituted aminocarbonylamino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-24a) 
(wherein, R1-2-24a and R2-2-24a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-24a(s) and R2-2-24a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing isocyanate.
This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-7) in [7].
[25] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino, i.e., the compounds of the present invention of the formula (I-2-25) 
(wherein, R1-2-25 and R2-2-25 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-25(s) and R2-2-25(s) is a substituted oxycarbonylamino or a group containing a substituted oxyocarbonylamino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the formula (I-2-25a) 
(wherein, R1-2-25a and R2-2-25a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-25a(s) and R2-2-25a(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing haloformic acid ester.
This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-9) in [9].
[26] The compounds of the present invention of the formula (I-1) in which at least one of R1(s) or R2(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy, i.e., the compounds of the present invention of the formula (I-2-26) 
(wherein, R1-2-26 and R2-2-25 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-26(s) and R2-2-26(s) is a substituted oxycarbonyloxy or a group containing a substituted oxycarbonyloxy and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a hydroxy or a group containing hydroxy, i.e., the compounds of the formula (I-2-26a) 
(wherein, R1-2-26a and R2-2-26a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-26a(S) and R2-2-26a(s) is a hydroxy or a group containing hydroxy and the other symbols are the same meaning as hereinbefore described.) and the corresponding compounds containing haloformic acid ester.
This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-9) in [9].
[27] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted (hydroxy)methyl or a group containing substituted (hydroxy)methyl, i.e., the compounds of the present invention of the formula (I-2-27) 
(wherein, R1-2-27 and R2-2-27 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-27(s) and R2-2-27(s) is a substituted (hydroxy)methyl or a group containing a substituted (hydroxy)methyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by reacting the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a formyl, i.e., the compounds of the formula (I-2-27a) 
(wherein, R1-2-27a and R2-2-27a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-27a(s) and R2-2-27a(s) is a formyl and the other symbols are the same meaning as hereinbefore described.) and Grignard""s reagents or corresponding derivatives containing lithium.
This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-11a) in [11].
[28] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a substituted carbonyl or a group containing a substituted carbonyl, i.e., the compounds of the present invention of the formula (I-2-28) 
(wherein, R1-2-28 and R2-2-28 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-28(s) and R2-2-28(s) is a substituted carbonyl or a group containing a substituted carbonyl and the other symbols are the same meaning as hereinbefore described.) may be prepared by oxidizing the said compounds of the formula (I-2-27).
This reaction may be carried out by the same procedure for preparation of the compounds of the formula (I-1-12) in [12].
[29] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is an amino or a group containing amino, i.e., the compounds of the present invention of the formula (I-2-29) 
(wherein, R1-2-29 and R2-2-29 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-29(s) and R2-2-29(s) is an amino or a group containing amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by reduce of nitro in the compounds of the formula (I-2) in which at least one of R1(s) or R2(s) is a nitro or a group containing nitro, i.e., the compounds of the formula (I-2-29a) 
(wherein, R1-2-29a and R2-2-29a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-29a(s) and R2-2-29a(s) is a nitro or a group containing nitro and the other symbols are the same meaning as hereinbefore described.).
The reduction of nitro may be carried out by the same procedure for preparation of the compounds of the formula (I-1-13) in [13].
[30] The compounds of the present invention of the formula (I-2) in which at least one of R1(s) or R2(s) is a xe2x80x94COOH, hydroxy or amino or a group containing xe2x80x94COOH, hydroxy or amino, i.e., the compounds of the present invention of the formula (I-2-30) 
(wherein, R1-2-30 and R2-2-30 are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-30(s) and R2-2-30(s) is a xe2x80x94COOH, hydroxy or amino or a group containing xe2x80x94COOH, hydroxy or amino and the other symbols are the same meaning as hereinbefore described.) may be prepared by removal of protecting group in the compounds of the formula (I-2) in which xe2x80x94COOH, hydroxy or amino which is protected by a protecting group or a group containing xe2x80x94COOH, hydroxy or amino which is protected by a protecting group, i.e., the compounds of the formula (I-2-30a) 
(wherein, R1-2-30a and R2-2-30a are the same meanings as hereinbefore described for R1 and R2, respectively, provided that at least one of R1-2-30a(s) and R2-2-30a(s) is a protected xe2x80x94COOH (e.g., it is protected by methyl, ethyl, t-butyl and benzyl etc.), protected hydroxy (e.g., it is protected by methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, benzyl etc.) or protected amino (e.g., it is protected by benzyloxycarbonyl, t-butoxycarbonyloxy, trifluoroacetyl etc.) or a group containing such a group and the other symbols are the same meaning as hereinbefore described.) by an alkaline hydrolysis, by removal of protecting group in an acidic condition, by removal of silyl or by removal of protecting group based on hydrogenelysis. An alkaline hydrolysis, by removal of protecting group in an acidic condition, by removal of silyl or by hydrogenolysis may be carried out by same procedure for preparation of the compounds of the formula (I-1-14) in [14].
Reaction for removal of protecting group in the present invention means an ordinal one which is well known to the person in the art, for example, alkaline hydrolysis, removal of protecting group in an acidic condition and hydrogenolysis. The aimed compounds of the present invention may be prepared easily by choice of these reactions.
As well known to the person in the art, a protecting group of carboxy includes, for example, methyl, ethyl, t-butyl and benzyl. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991.
A protecting group of hydroxy includes, for example, methoxymethyl, tetrahydropyranyl, t-butyldimethylsilyl, acetyl, and benzyl. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991.
A protecting group of amino includes, for example, benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991.
The compounds of the formula (V) are known per se or may be prepared according to the following Reaction Scheme or by known methods easily.
In Reaction Scheme, X is halogen. 
The compounds of the formulae (III), (IV), (VI), (VII) or (VIII) used as starting materials have been known per se or may be prepared by known methods easily.
Further, the compounds of the formula (I-1-1c) in which A is benzene, Rxe2x80x2 is carboxy, p is 1 and Rxe2x80x2 is bonded at 4-position, i.e., the compounds of the formula (XI) are important intermediates of the compounds of the formula (I) of the present invention. The methods for preparation of the compounds of the formula (XI) are shown in the mentioned Reaction Scheme 5. Next, each step is explained in detail.
The reaction to synthesis of the compounds of the formula (XIII) from the compounds of the formula (XII) is well known. For example, it may be carried out in an inert organic solvent (acetonitrile, benzene, toluene, xylene, methyhlene chloride, chloroform, dimethoxy ethane, tetrahydrofuran, tetrahydropyran, dioxane, diethyl ether, acetone etc.) or mixture thereof, in the presence of Lewis acid (Znl2, ZnCl2, aluminum chloride, TiCl2, lithium hypochloric acid, lithium borotetrafluoride, lithium hexafluoride etc.) and cyanide derivatives (trimethylsilylcyanide, diethyl aluminum cyanide, or diethyl cyanophosphonate etc.) at 0xcx9c40xc2x0 C.
The reaction to synthesis of the compounds of the formula (XIV) from the compounds of the formula (XIII) is well known. For example, it may be carried out in an inert organic solvent (benzene, toluene, ethyl acetate, dioxane, dimethoxy ethane, diethyl ether, tetrahydrofuran, tetrahydropyran, the mixture thereof etc.) in the presence of oxidant (2,3-dichloro-5,6-dicyano-1,4-benzoquinon, chloranil (2,3,5,6-tetrachloro-1,4-benzoquinon) etc.) at room temperature to refluxing temperature. Or it may be carried out, for example, in an organic solvent (ethylene glycol, oleic acid, diethylene glycol, dimethyl ether, toluene, benzene, xylene etc.) in the presence of hydrogen acceptor (nitrobenzene, maleic acid, cyclohexen, oleic acid, 1,5-cycloctadien, phenylacetylene, 2-butylic acid etc.) and in the presence of metal catalyst (Pdxe2x80x94C, palladium hydroxide, palladium black, Pd, platinum oxide, Ni, Raney nickel, ruthenium chloride etc.) at 60xc2x0 C.xcx9crefluxing temperature.
The reaction to synthesis of the compounds of the formula (XI) from the compounds of the formula (XIV) is well known. For example, it may be carried out in alcohol solvent (ethylene glycol, t-butanol, benzyl alcohol, methanol, ethanol, propanol, isopropanol etc.) in the presence of alkali (sodium hydroxide, potassium hydroxide, lithium hydroxide etc.) at 60xc2x0 C.xcx9crefluxing temperature.
In each reaction in the present specification, obtained products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, by thin layer chromatography or by column chromatography using silica gel or magnesium silicate, by washing or by recrystallization. Purification may be carried out after each reaction, or after a series of reactions.
In addition, the optical isomers of the compounds of the present invention of the formula (I) may be obtained by an ordinal optical separation (e.g., separation by gas chromatography or by high performance liquid chromatography, separation by crystallization to diastermeric salt or clathrate compounds or separation by preferential crystallization etc.) or by ordinal method for preparation of racemic compound.
[Pharmacological Activities]
According to the following experiments, it has been proved that the compounds of the present invention of the formula (I) possess inhibitory activities of producing IL-6 and/or IL-12.
(1) Assaying Inhibitory Activity on IL-6 Production and Cellular Toxicity
[Experimental Method]
1.5xc3x97104 of A549 cells (human lung epithelial cell line) were suspended in dalbeco-modified eagle medium (DMEM) containing 0.5% fetus bovine serum (abbreviated as FBS)xcx9c(100 xcexcl) and incubated in 96 well-microplate over day and night. The test compound dissolved in various kinds of solvents at various concentrations (20 xcexcl) and Tumor Necrosis Factor-xcex1 (TNF-xcex1 (Genzyme Co, Cat. No. TNF-H)) dissolved in DMEM at the concentration of 12.5 ng/ml (80 xcexcl) were added thereto. After incubation for 24 hours, the supernatant (200 xcexcl) was recovered to assay the quantity of IL-6 using Enzyme Linked Immuno Solvent Assay (ELISA) Method (RandD Systems Co., Cat. No. D6050), to calculate inhibitory activity of the test compound and determine 50% inhibitory concentration (IC50). To the cells from which the supernatant was removed, a solution of brom 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolinium (abbreviated as MTT (Dojin Chemical Laboratory, Cat. No. 345-01821)) dissolved in DMEM containing 10% FBS at the concentration of 0.5 mg/ml (100 xcexcl) was added and incubated for 3 hours. After removing MTT solution, methanol (100 xcexcl) was added thereto. After lyse the cells, the intensity of absorbance on 570 nm as a control of 690 nm was determined to assay cellular toxicity of the test compound. As a result, it has been proved that the compounds of the present invention possess an inhibitory activity on IL-6 production with an IC50 value of 20 xcexcM or less. For example, free compound of the compound of Example 20(4) possessed an inhibitory activity on IL-6 production with an IC50 value of 4.4 xcexcM and showed no cellular toxicity at 10 xcexcM.
(2) Assaying Inhibitory Activity on IL-12 Production and Cellular Toxicity
[Experimental Method]
2.0xc3x97105 of peripheral monocyte prepared from healthy human blood by Ficole gravity centrifugation method (Pharmacia Biotech Co, Cat. No. 17-1440-02) were suspended in RPMI1640 medium containing 10% FBS (170 xcexcl). The test compound dissolved in various kinds of solvents at the various concentrations (10 xcexcl) and 6000 units/ml of Interferon-xcex3 (IFN-xcex3 (Serotec Co, Cat. No. PHP050)) (10 xcexcl) dissolved in RPMI1640 medium containing 10% FBS. After incubation for 24 hours in 96 well-microplate, lipopolysaccharide (6 xcexcg/ml) dissolved in RPMI1640 medium containing 10% FBS (LPS (Difco Co., Cat. No. 3120-25-0)) (10 xcexcl) was added thereto. After incubation for 20 hours, the supernatant (150 xcexcl) was recovered to assay the quantity of IL-12 using ELISA Method (RandD Systems Co, Cat. No. D1200), calculate for inhibitory activity of the test compound and determine 50% inhibitory concentration (IC50) (see J. Exp. Med., 183, 147 (1996)). To the cells from which the supernatant (150 xcexcl) was removed, a solution of MTT dissolved in RPMI1640 medium containing 10% FBS at 1 mg/ml (50 xcexcl) was added and incubated for 3 hours. 2-Propanol containing 0.04N HCl (100 xcexcl) was added thereto. After lyse the cells, the intensity of absorbance on 570 nm as a control of 690 nm was determined to assay cellular toxicity of the test compound. As a results, it has been proved that the compounds of the present invention possess an inhibitory activity on IL-12 production with an IC50 value of 10 xcexcM or less. For example, hydrochloride of the compound of Example 20(4) possessed an inhibitory activity on IL-12 production with an IC50 of 0.11 xcexcM and showed no cellular toxicity at 1 xcexcM.
[Toxicity]
The toxicity of the compounds of the present invention is very low and therefore, it is confirmed that these compounds are safe for use as medicine.
[Application for Pharmaceuticals]
The compounds of the present invention possess an inhibitory activity of producing IL-6 and/or IL-12 in animal, especially human, so they are useful for prevention and/or treatment of, for example, various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi""s sarcoma, rheumatoid arthritis, gammopathy, Castleman""s disease, atrial myxoma, diabetes mellitus, autoimmune diseases, hepatitis, multiple sclerosis, colitis, graft versus host immune diseases, infectious diseases.
For the purpose above described, the compounds of the general formula (I) of the present invention, non-toxic salts, acid addition salts, or hydrates thereof may be normally administered systematically or locally, usually by oral or parenteral administration.
The doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 0.1 mg and 100 mg, by parenteral administration (preferred into vein) up to several times per day, or continuous administration between 1 and 24 hrs. per day into vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered as inner solid compositions or inner liquid compositions for oral administration, or as injections, liniments or suppositories etc. for parenteral administration.
Inner solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules. Capsules contain hard capsules and soft capsules.
In such inner solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent (lactose, mannitol, glucose, microcrystalline cellulose, starch etc.), connecting agents (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.), disintegrating agents (cellulose calcium glycolate etc.), lubricating agents (magnesium stearate), stabilizing agents, assisting agents for dissolving (glutamic acid, asparaginic acid etc.) etc. to prepare pharmaceuticals by known methods. The pharmaceuticals may, if desired, be coated with material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Inner liquid compositions for oral administration include pharmaceutically-acceptable water-agents, emulsions, syrups and elixirs etc. In such liquid compositions, one or more of the active compound(s) is or are comprised in inert diluent(s) commonly used in the art (purified water, ethanol or mixture thereof etc.). Besides inert diluents, such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening agents, flavouring agents, perfuming agents and preserving agents.
Injections for parenteral administration include solutions, suspensions and emulsions, and solid injections. Aqueous solutions or suspensions include distilled water for injection and physiological salt solution. Non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, plant oil such as olive oil, alcohol such as ethanol, POLYSOLBATE80 (registered trade mark) etc. Such compositions may comprise additional diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent, assisting agents such as assisting agents for dissolving (for example, glutamic acid, asparaginic acid). They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions and which can be dissolved in sterile water or some other sterile diluent for injection immediately before use.
Other compositions for parenteral administration include liquids for external use, and endermic liniments, ointments, spray, suppositories and pessaries which comprise one or more of the active compound(s) and may be prepared by known methods.
Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate, stabilizing agents to give isotonicity, isotonic buffer such as sodium chloride, sodium citrate, citric acid. For preparation of such spray compositions, for example, the method described in the U.S. Pat. Nos. 2,868,691 or 3,095,355 may be used.
The following reference Examples and Examples are intended to illustrate, but do not limit the present invention.
The solvents in parenthesis show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations. The solvents in parentheses in NMR show the solvents used for measurement.